The Human Correlation Core will serve to bridge the gap between mouse models and humans. This Core will analyze a number of the newly discovered murine immune regulatory genes using primary immune cells from normal human donors. The genes will be knocked down in primary human monocytes and in CD4, CDS and B-lymphocytes using lentivirus delivered shRNA. The cells will then be challenged with relevant NIAID category A, B and C priority pathogens or with purified immune agonists, as suggested by the murine studies. The effect of each gene on the production of cytokines and eicosanoids, on signaling pathways, and on global transcriptional responses will be measured using a variety of techniques in collaboration with the Systems Biology and CyTOF cores. In collaboration with the Bioinformatics Core, the effect of these genes on immune regulatory networks will be characterized. The Human Correlation Core will monitor the growing compendium of human variants in genes of unknown function that have been associated with infectious, immune, or inflammatory disease. Mice bearing ENU induced mutations in orthologs of these genes will be bred to homozygosity, thereby providing an animal model for determining the mechanism underlying the human disease.